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How to Manage Refractory Gastroesophageal Reflux Disease

  • Authors: Joel E Richter, MD
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Target Audience and Goal Statement

This activity is intended for primary care clinicians, gastroenterologists, and other specialists who care for patients with gastroesophageal reflux disease.

The goal of this activity is to review the causes of refractory gastroesophageal reflux disease with and without esophagitis and define appropriate management strategies for differential diagnosis and treatment.

  1. Identify the percentage of patients who do not respond to first-line treatment for gastroesophageal reflux disease (GERD)
  2. Define refractory GERD
  3. Describe the most appropriate first step in the investigation of refractory GERD
  4. List most likely diagnoses that account for refractory GERD with esophagitis
  5. Identify appropriate tests for investigating refractory GERD after endoscopy


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  • Joel E Richter, MD

    Chair, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania


    Disclosure: Joel E. Richter, MD, has disclosed associations with the following companies: AstraZeneca and Tap. See the article online for full details of the relationships.

CME Author(s)

  • Désirée Lie, MD, MSEd

    Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California


    Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.

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How to Manage Refractory Gastroesophageal Reflux Disease

Authors: Joel E Richter, MDFaculty and Disclosures


Summary and Introduction


Patients who are unresponsive to 4–8 weeks' treatment with PPIs twice daily might have so-called refractory GERD. The first investigation these patients should undergo is upper endoscopy to exclude a diagnosis of peptic ulcer disease or cancer and identify the presence of esophagitis. The presence of esophagitis in these patients is suggestive of a pill-induced injury, an autoimmune skin disease involving the esophagus, eosinophilic esophagitis or, less likely, a hypersecretory syndrome or a genotype that confers altered metabolism of PPIs. Refractory reflux syndromes associated with normal endoscopy findings are more problematic to diagnose and further testing may be required, including prolonged 48 h pH testing, impedance measurements (for nonacid reflux), esophageal manometry and gastric function tests. For patients with refractory GERD who do not have esophagitis, possible etiologies include nocturnal gastric acid breakthrough, nonacid GER, missed GER or other diseases such as achalasia, gastroparesis or functional heartburn.


Medical therapy for GERD has improved remarkably since the introduction of PPIs in the late 1980s; however, some patients still do not respond as expected to the therapy currently available. Despite twice-daily dosing of PPIs, reflux symptoms can persist, new symptoms can occur or be unmasked, and esophagitis can fail to heal. Some patients with unresponsive GERD might not take their medications. The unresponsiveness of the disease might also be caused by nonacid reflux, or be contributed to by welldefined pharmacokinetic factors. In addition, the esophagitis and/or symptoms present might not be caused by acid reflux. Management of the difficult-to-treat ('refractory') reflux patient can, therefore, be a challenge for the clinician. This Review considers the initial treatment of patients with GERD, the diagnostic approach to refractory GERD, and the diagnoses possible in patients with refractory GERD in the presence and absence of esophagitis.